David A. Gewirtz, Ph.D.

Professor

David A. Gewirtz, Ph.D.

Department: Department of Pharmacology and Toxicology

Phone: (804) 828-9523

Fax: (804) 827-1134

Email: david.gewirtz@vcuhealth.org

Address/Location:
Massey Cancer Center
401 College Street
Goodwin Research Laboratories, Room 321
Box 980035
Richmond,

Education

  • City University of New York, Mt. Sinai, 1977.

Research interests

  • Biochemical and molecular effects of antitumor drugs and radiation in breast tumor cells and lung cancer cells.
  • Regulation of senescence arrest.
  • Involvement of autophagy in sensitivity and resistance to chemotherapy and radiation.
  • Mitigation of the toxicity of antitumor drugs.

Senescence and Tumor Dormancy
Breast tumor cells and non-small cell lung cancer cells fail to undergo apoptotic cell death in response to either radiation or antitumor drugs such as Adriamycin and etoposide, instead demonstrating a prolonged growth arrest (Fornari et al, 1996; Watson et al, 1997). Consequently, tumor cells that remain dormant for an extended time period may ultimately recover, leading to disease recurrence. Current research efforts are directed at the development of approaches for promoting cell death in order to (i) enhance the response of breast and lung tumor cells to radiation and chemotherapy and (ii) prevent recovery of proliferative function. 

Regulation of senescence arrest
Our studies suggests that prolonged growth arrest in p53 wild-type cells exposed to either adriamycin or radiation reflects replicative senescence (induction of p53 and p21, and expression of the senescence marker, beta-galactosidase); in contrast, non-senescent growth arrest in p53 mutant cells is succeeded by a wave of apoptotic cell death (Elmore et al, 2002). We are continuing to investigate both biochemical and molecular regulation of senescence arrest and the basis for recovery of proliferative function in a subpopulation of the arrested cells (Elmore et al, 2005; Jones et al, 2005).

Involvement of autophagy in sensitivity and resistance to chemotherapy and radiation.
Although there is extensive evidence for a cytoprotective form of autophagy, our laboratory has also identified a nonprotective function of autophagy that, in the case of radiation, is associated with the loss of functional p53 (Chakradeo et al, 2015; Bristol et al, 2013). Our current studies are designed to understand the biochemical and molecular basis for the different functions of autophagy as well as to establish that autophagy is not actually a mechanism of drug or radiation resistance.

Mitigation of the toxicity of antitumor drugs
Our laboratory, in association with that of other members of the department, has initiated a program to understand the basis for the toxicity of drugs such as the taxanes and platinum based compounds in terms of peripheral neuropathy and potentially cognitive dysfunction. This work is being performed in collaboration with the laboratories of Dr. Imad Damaj and Aron Lichtman. It is anticipated that studies will be extended to address cancer cachexia, cancer pain and the arthralgia induced by aromatase inhibitors.

Selected publications

  1. Gewirtz DA, Tyutyunyk-Massey L, Landry JW. The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy. Biochem Pharmacol. 2018; Epub ahead of print, DOI: 10.1016/j.bcp.2018.01.048.  
  2. Kyte SL, Toma W, Bagdas D, Meade JA, Schurman LD, Lichtman AH, Chen ZJ, Del Fabbro E, Fang X, Bigbee JW, Damaj MI, Gewirtz DA. Nicotine prevents and reverses paclitaxel-induced mechanical allodynia in a mouse model of CIPN. J Pharmacol Exp Ther. 2018; 364(1):110-119. PMCID: PMC5738719.
  3. Xu J, Patel NH, Saleh T, Cudjoe EK, Jr., Alotaibi M, Wu Y, Lima S, Hawkridge AM, Gewirtz DA. Differential radiation sensitivity in p53 wild-type and p53-deficient tumor cells associated with senescence but not apoptosis or (nonprotective) autophagy. Radiat Res. 2018; 190(5):538-557. PMCID PMC7141768.
  4. Curry ZA, Wilkerson JL, Bagdas D, Kyte SL, Patel N, Donvito G, Mustafa MA, Poklis JL, Niphakis MJ, Hsu KL, Cravatt BF, Gewirtz DA, Damaj MI, Lichtman AH. Monoacylglycerol lipase inhibitors reverse paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy. J Pharmacol Exp Ther. 2018; 366(1):169-183. PMCID PMC6038031. 
  5. Gewirtz DA, Tyutyunyk-Massey L, Landry JW. The potentially conflicting cell autonomous and cell non-autonomous functions of autophagy in mediating tumor response to cancer therapy. Biochem Pharmacol. 2018; 153:46-50.  
  6. Toma W, Kyte SL, Bagdas D, Jackson A, Meade JA, Rahman F, Chen ZJ, Del Fabbro E, Cantwell L, Kulkarni A, Thakur GA, Papke RL, Bigbee JW, Gewirtz DA, Damaj MI. The alpha7 nicotinic receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy in mice without tolerance or altering nicotine reward and withdrawal. Exp Neurol. 2019; 320:113010. PMCID PMC6708482. 
  7. Saleh T, Tyutyunyk-Massey L, Murray GF, Alotaibi MR, Kawale AS, Elsayed Z, Henderson SC, Yakovlev V, Elmore LW, Toor A, Harada H, Reed J, Landry JW, Gewirtz DA. Tumor cell escape from therapy-induced senescence. Biochem Pharmacol. 2019; 162:202-212.  
  8. Patel NH, Xu J, Saleh T, Wu Y, Lima S, Gewirtz DA. Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells. Biochem Pharmacol. 2020; 175:113896.
  9. Gewirtz DA. The switch between protective and nonprotective autophagy; implications for autophagy inhibition as a therapeutic strategy in cancer. Biology (Basel). 2020; 9(1). PMCID PMC716829
  10. Patel NH, Xu J, Saleh T, Wu Y, Lima S, Gewirtz DA. Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells. Biochem Pharmacol. 2020; 175:113896.  
  11. Saleh T, Carpenter VJ, Tyutyunyk-Massey L, Murray G, Leverson JD, Souers AJ, Alotaibi MR, Faber AC, Reed J, Harada H, Gewirtz DA. Clearance of therapy-induced senescent tumor cells by the senolytic abt-263 via interference with bcl-xl -bax interaction. Mol Oncol. 2020; 14(10):2504-2519. PMCID PMC7530780. 
  12. Patel NH, Sohal SS, Manjili MH, Harrell JC, Gewirtz DA. The roles of autophagy and senescence in the tumor cell response to radiation. Radiat Res. 2020; 194(2):103-115. PMCID PMC7482104. 

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